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Candidates for prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT) of metastatic castration-resistant prostate cancer (mCRPC) frequently have “mismatch” lesions with pronounced 18-fluorodeoxyglucose ([ 18 F]FDG) but attenuated PSMA ligand uptake on positron emission tomography (PET). However, no quantitative criteria yet exist to identify mismatch lesions and predict their response to RLT. To define such criteria, we retrospectively analyzed 267 randomly-selected glucometabolic mCRPC metastases from 22 patients. On baseline PET, we determined [ 18 F]FDG and [ 68 Ga]Ga-PSMA-11 maximum standardized uptake value (SUV max ), and calculated the [ 18 F]FDG SUV max /[ 68 Ga]Ga-PSMA-11 SUV max quotient (FPQ). From follow-up [ 18 F]FDG PET after two lutetium-177-PSMA-617 RLT cycles, we evaluated the treatment response and categorized the lesions into three subgroups (partial remission, stable disease, progression) based on change in [ 18 F]FDG SUV max . Lastly, we compared the baseline PET variables in progressing versus non-progressing lesions. Variables differing significantly, and a score incorporating them, were assessed via receiver operator characteristic (ROC) curve analysis, regarding ability to predict lesional progression, with area under the curve (AUC) as metric. Cut-offs with optimal sensitivity and specificity were determined using the maximum value of Youden's index. Fifty-one of 267 lesions (19.1%) progressed, 102/267 (38.2%) manifested stable disease, and 114/267 (42.7%) partially responded after two RLT cycles. At baseline, median [ 68 Ga]Ga-PSMA-11 SUV max was significantly lower ( p  < 0.001), median FPQ significantly higher ( p  < 0.001), and median [ 18 F]FDG SUV max similar in progressing versus non-progressing lesions. [ 68 Ga]Ga-PSMA-11 SUV max and FPQ showed predictive power regarding progression (AUCs: 0.89, 0.90). An introduced clinical score combining both further improved predictive performance (AUC: 0.94). Optimal cut-offs to foretell progression were: [ 68 Ga]Ga-PSMA-11 SUV max  < 11.09 (88.2% sensitivity, 81.9% specificity), FPQ ≥ 0.92 (90.2% sensitivity, 78.7% specificity), clinical score ≥ 6/9 points (88.2% sensitivity, 87.5% specificity). At baseline, a low [ 68  Ga]Ga-PSMA-11 SUV max and a high FPQ predict early lesional progression under RLT; [ 18 F]FDG SUV max does not. A score combining [ 68  Ga]Ga-PSMA-11 SUV max and FPQ predicts early lesional progression even more effectively and might therefore be useful to quantitatively identify mismatch lesions.

Background Positron emission tomography/computed tomography (PET/CT) using prostate-specific membrane antigen (PSMA)-targeted radiotracers labeled with zirconium-89 ( 89 Zr; half-life ~ 78.41 h) showed promise in localizing biochemical recurrence of prostate cancer (BCR) in pilot studies. Methods Retrospective analysis of 38 consecutive men with BCR (median [minimum–maximum] prostate-specific antigen 0.52 (0.12–2.50 ng/mL) undergoing [ 89 Zr]Zr-PSMA-617 PET/CT post-negative [ 68 Ga]Ga-PSMA-11 PET/CT. PET/CT acquisition 1-h, 24-h, and 48-h post-injection of a median (minimum–maximum) [ 89 Zr]Zr-PSMA-617 tracer activity of 123 (84–166) MBq. Results [ 89 Zr]Zr-PSMA-617 PET/CT detected altogether 57 lesions: 18 local recurrences, 33 lymph node metastases, 6 bone metastases in 30/38 men with BCR (78%) and prior negative conventional PSMA PET/CT. Lesion uptake significantly increased from 1-h to 24-h and, in a majority of cases, from 24-h to 48-h. Tumor-to-background ratios significantly increased over time, with absolute increases of 100 or more. No side effects were noted. After [ 89 Zr]Zr-PSMA-617 PET/CT-based treatment, prostate-specific antigen concentration decreased in all patients, becoming undetectable in a third of patients. Limitations: retrospective, single center design; infrequent histopathological and imaging verification. Conclusion This large series provides further evidence that [ 89 Zr]Zr-PSMA-617 PET/CT is a beneficial imaging modality to localize early BCR. A remarkable increase in tumor-to-background ratio over time allows localization of tumor unidentified on conventional PSMA PET/CT.

Background The state-of-the-art method for imaging men with biochemical recurrence of prostate cancer (BCR) is prostate-specific membrane antigen (PSMA)-targeted positron emission tomography/computed tomography (PET/CT) with tracers containing short-lived radionuclides, e.g., gallium-68 ( 68 Ga; half-life: ∼67.7 min). However, such imaging not infrequently yields indeterminate findings, which remain challenging to characterize. PSMA-targeted tracers labeled with zirconium-89 ( 89 Zr; half-life: ∼78.41 h) permit later scanning, which may help in classifying the level of suspiciousness for prostate cancer of lesions previously indeterminate on conventional PSMA-targeted PET/CT. Methods To assess the ability of [ 89 Zr]Zr-PSMA-617 PET/CT to characterize such lesions, we retrospectively analyzed altogether 20 lesions that were indeterminate on prior [ 68 Ga]Ga-PSMA-11 PET/CT, in 15 men with BCR (median prostate-specific antigen: 0.70 ng/mL). The primary endpoint was the lesions’ classifications, and secondary endpoints included [ 89 Zr]Zr-PSMA-617 uptake (maximum standardized uptake value [SUV max ]), and lesion-to-background ratio (tumor-to-liver ratio of the SUV max [TLR]). [ 89 Zr]Zr-PSMA-617 scans were performed 1 h, 24 h, and 48 h post-injection of 123 ± 19 MBq of radiotracer, 35 ± 35 d post-[ 68 Ga]Ga-PSMA-11 PET/CT. Results Altogether, 6/20 previously-indeterminate lesions (30%) were classified as suspicious (positive) for prostate cancer, 14/20 (70%), as non-suspicious (negative). In these two categories, [ 89 Zr]Zr-PSMA-617 uptake and lesional contrast showed distinctly different patterns. In positive lesions, SUV max and TLR markedly rose from 1 to 48 h, with SUV max essentially plateauing at high levels, and TLR further steeply increasing, from 24 to 48 h. In negative lesions, uptake, when present, was very low, and decreasing, while contrast was minimal, from 1 to 48 h. No adverse events or clinically-relevant vital signs changes related to [ 89 Zr]Zr-PSMA-617 PET/CT were noted during or ~ 4 weeks after the procedure. Conclusions In men with BCR, [ 89 Zr]Zr-PSMA-617 PET/CT may help characterize as suspicious or non-suspicious for prostate cancer lesions that were previously indeterminate on [ 68 Ga]Ga-PSMA-11 PET/CT. Trial registration Not applicable.

Purpose Preliminary data from retrospective analyses and recent data from large randomized controlled trials suggest safety and efficacy of radioligand therapy (RLT) targeting prostate-specific membrane antigen (PSMA) in men with metastatic castration-resistant prostate cancer (mCRPC). Limited data on this modality have been published regarding large samples treated in everyday practice. Methods We analyzed prospectively collected registry data regarding lutetium-177 ( 177 Lu)-PSMA-617 RLT of 254 consecutive men with mCRPC seen in everyday academic practice. Since 177 Lu-PSMA-617 was experimental salvage treatment following failure of individually appropriate conventional therapies, patients were generally elderly and heavily pretreated (median age 70 years; prior taxanes 74.0%, 188/254), with late–end-stage disease (visceral metastasis in 32.7%, 83/254). Primary endpoints were response to RLT, defined by changes from baseline serum prostate-specific antigen (PSA) concentration, PSA progression-free survival (PSA-PFS), and overall survival (OS), estimated with Kaplan–Meier statistics, and caregiver-reported and patient-reported safety. Unless noted, median (minimum–maximum) values are given. Results Patients received 3 (1–13) 177 Lu-PSMA-617 activities (6.5 [2.5–11.6] GBq/cycle) every 5.7 (3.0–11.0) weeks. Best response was ≥ 50% PSA reduction in 52.0% of patients (132/254). PSA-PFS was 5.5 (95% confidence interval [95%CI] 4.4–6.6) months and OS, 14.5 (95%CI 11.5–17.5) months. In multivariable Cox proportional-hazards modeling, response to the initial ≤ 2 RLT administrations was the strongest significant prognosticator related to OS (hazard ratio 3.7 [95%CI 2.5–5.5], p  < 0.001). No RLT-related deaths or treatment discontinuations occurred; the most frequent RLT-related Grade 3/4 adverse events were anemia (18/254 patients, 7.1%), thrombocytopenia (11/254, 4.3%), and lymphopenia (7/254, 2.8%). RLT-related xerostomia, all grade 1/2, was noted in 53/254 (20.9%). Conclusions In a large, prospectively observed “real-world” cohort with late-stage/end-stage mCRPC and conventional treatment failure, 177 Lu-PSMA-617 RLT was effective, safe, and well-tolerated. Early biochemical disease control by such therapy was associated with better OS. Prospective study earlier in the disease course may be warranted.

Idiopathic pulmonary fibrosis (IPF) is a lethal fibrosing interstitial lung disease with a mean survival time of less than 5 years. Nonspecific presentation, a lack of effective early screening tools, unclear pathobiology of early-stage IPF and the need for invasive and expensive procedures for diagnostic confirmation hinder early diagnosis. In this study, we introduce a new screening tool for IPF in primary care settings that requires no new laboratory tests and does not require recognition of early symptoms. Using subtle comorbidity signatures identified from the history of medical encounters of individuals, we developed an algorithm, called the zero-burden comorbidity risk score for IPF (ZCoR-IPF), to predict the future risk of an IPF diagnosis. ZCoR-IPF was trained on a national insurance claims database and validated on three independent databases, comprising a total of 2,983,215 participants, with 54,247 positive cases. The algorithm achieved positive likelihood ratios greater than 30 at a specificity of 0.99 across different cohorts, for both sexes, and for participants with different risk states and history of confounding diseases. The area under the receiver-operating characteristic curve for ZCoR-IPF in predicting IPF exceeded 0.88 and was approximately 0.84 at 1 and 4 years before a conventional diagnosis, respectively. Thus, if adopted, ZCoR-IPF can potentially enable earlier diagnosis of IPF and improve outcomes of disease-modifying therapies and other interventions. A machine learning algorithm can predict the future risk of idiopathic pulmonary fibrosis, a disease that is difficult to diagnose at its early stages, based on comorbidity signatures in electronic health records.

RationaleIn patients with biochemical recurrence of prostate cancer (BCR), preliminary data suggest that prostate-specific membrane antigen (PSMA) ligand radiotracers labeled with zirconium-89 (89Zr; half-life ~ 78.41 h), which allow imaging ≥ 24 h post-injection, detect suspicious lesions that are missed when using tracers incorporating short-lived radionuclides.Materials and methodsTo confirm [89Zr]Zr-PSMA-617 positron emission tomography/computed tomography (PET/CT) detection efficacy regarding such lesions, and compare quality of 1-h, 24-h, and 48-h [89Zr]Zr-PSMA-617 scans, we retrospectively analyzed visual findings and PET variables reflecting lesional [89Zr]Zr-PSMA-617 uptake and lesion-to-background ratio. The cohort comprised 23 men with BCR post-prostatectomy, median (minimum–maximum) prostate-specific antigen (PSA) 0.54 (0.11–2.50) ng/mL, and negative [68Ga]Ga-PSMA-11 scans 40 ± 28 d earlier. Primary endpoints were percentages of patients with, and classifications of, suspicious lesions.ResultsAltogether, 18/23 patients (78%) had 36 suspicious lesions (minimum–maximum per patient: 1–4) on both 24-h and 48-h scans (n = 33 lesions) or only 48-h scans (n = 3 lesions). Only one lesion appeared on a 1-h scan. Lesions putatively represented local recurrence in 11 cases, and nodal or bone metastasis in 21 or 4 cases, respectively; 1/1 lesion was histologically confirmed as a nodal metastasis. In all 15 patients given radiotherapy based on [89Zr]Zr-PSMA-617 PET/CT, PSA values decreased after this treatment. Comparison of PET variables in 24-h vs 48-h scans suggested no clear superiority of either regarding radiotracer uptake, but improved lesion-to-background ratio at 48 h.ConclusionsIn men with BCR and low PSA, [89Zr]Zr-PSMA-617 PET/CT seems effective in finding prostate malignancy not seen on [68Ga]Ga-PSMA-11 PET/CT. The higher detection rates and lesion-to-background ratios of 48-h scans versus 24-h scans suggest that imaging at the later time may be preferable. Prospective study of [89Zr]Zr-PSMA-617 PET/CT is warranted.

Purpose Concern is growing about long-term side effects of differentiated thyroid cancer treatment, most notably radioactive iodine (RAI) therapy. However, published studies on the subject have had heterogeneous cohorts and conflicting results. This review seeks to provide an updated evaluation of published evidence, and to elucidate the risk of second primary malignancies (SPMs), especially secondary hematologic malignancies (SHMs), attributable to RAI therapy. Methods An extensive literature search was performed in Ovid MEDLINE, Ovid MEDLINE and In-Process & Other Non-Indexed Citations, Ovid MEDLINE Epub Ahead of Print, Cochrane Central Register of Controlled Trials (CENTRAL) and PubMed. Studies regarding RAI-induced SPMs or a dose–response relationship between RAI therapy and SPMs were identified, 10 of which were eligible for the analysis. We evaluated risk of bias in each study and judged quality of evidence (QOE) across all studies using the Grading of Recommendations, Assessment, Development and Evaluations approach. Results For the outcome “SPM”, the relative effect (relative risk, hazard ratio, or odds ratio) of RAI vs. no RAI ranged from 1.14 to 1.84 across studies, but most results were not statistically significant. For the outcome “SHM”, reported relative effects ranged from 1.30 to 2.50, with 2/3 of the studies presenting statistically significant results. In 7/8 of the studies, increased risk for SPM was shown with increasing cumulative RAI activity. QOE was “very low” regarding SPM after RAI and regarding a dose–response relationship, and “low” for SHM after RAI. Conclusion Based on low quality evidence, an excess risk for the development of SPM cannot be excluded but is expected to be small.

In biochemical recurrence of prostate cancer (BCR), prompt tumor localization guides early treatment, potentially improving patient outcomes. Gallium-68 prostate-specific membrane antigen-11 positron emission tomography/computed tomography (68Ga-PSMA-11 PET/CT) detection rates of lesions suspicious for prostate cancer are well known to rise along with prostate-specific antigen (PSA) concentration. However, published data are limited regarding very low values (≤0.2 ng/mL). We retrospectively analyzed ~7-year “real-world” experience in this setting in a large post-prostatectomy cohort (N = 115) from two academic clinics. Altogether 44 lesions were detected in 29/115 men (25.2%) (median [minimum–maximum] 1 [1–4]/positive scan). The apparent oligometastatic disease was found in nine patients (7.8%) at PSA as low as 0.03 ng/mL. Scan positivity rates were highest when PSA was >0.15 ng/mL, PSA doubling time was ≤12 months, or the Gleason score was ≥7b (in 83 and 107 patients, respectively, with available data); these findings were statistically significant (p ≤ 0.04), except regarding PSA level (p = 0.07). Given the benefits of promptly localizing recurrence, our observations suggest the potential value of 68Ga-PSMA-11 PET/CT in the very low PSA BCR setting, especially in cases with more rapid PSA doubling time or with high-risk histology.

“Tumor sink effects”, decreased physiological uptake of radiopharmaceuticals due to sequestration by a tumor, may impact radioligand therapy (RLT) toxicity and dosing. We investigated these effects with prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals in the healthy organs-at-risk (the parotid glands, kidneys, liver, and spleen) of 33 patients with metastatic castration-resistant prostate cancer (mCRPC). We retrospectively performed three intra-individual comparisons. First, we correlated changes from baseline to post-RLT (after two 177-lutetium (177Lu)-PSMA-617 cycles) in total lesional PSMA (∆TLP) and organ mean standardized uptake values (∆SUVmean). Second, in 25 RLT responders, we compared the organ SUVmean post-RLT versus that at baseline. Lastly, we correlated the baseline TLP and organ SUVmean. Data were acquired via 68-gallium-PSMA-11 positron emission tomography before the first and after the second 177Lu-PSMA-617 cycle. In the parotid glands and spleen, ∆TLP and ∆SUVmean showed a significant inverse correlation (r = −0.40, p = 0.023 and r = −0.36, p = 0.042, respectively). Additionally, in those tissues, the median organ SUVmean rose significantly from baseline after the response to RLT (p ≤ 0.022), and the baseline TLP and SUVmean were significantly negatively correlated (r = −0.44, p = 0.01 and r = −0.42, p = 0.016, respectively). These observations suggest tumor sink effects with PSMA-targeted radiopharmaceuticals in the salivary glands and spleen of patients with mCRPC.

Men with biochemical recurrence of prostate cancer (BCR) have increasing prostate-specific antigen (PSA) levels after potentially curative treatment, e.g., radical prostatectomy. Promptly finding these patients' sites of recurrence potentially allows earlier, better-targeted treatment. Gallium-68 prostate-specific membrane antigen-11 positron emission tomography/computed tomography ([sup.68] Ga-PSMA-11 PET/CT) imaging effectively localizes recurrence. However, this procedure's detection rate of lesions suspicious for prostate cancer increases along with patients' PSA levels, and limited published data describe performance when PSA is very low. We analyzed two academic institutions' ~7-year \"real-world\" experience with [sup.68] Ga-PSMA-11 PET/CT in 115 prostatectomized men with BCR with very low PSA (≤0.2 ng/mL). Altogether, 44 suspicious lesions (median [minimum-maximum] 1 [1-4]/patient) were found in 29/115 men (25.2%). Multiple lesions were detected in 9/115 (7.8%) at PSA concentrations as low as 0.03 ng/mL. [sup.68] Ga-PSMA-11 PET/CT thus appears to be useful even in BCR with very low PSA. In biochemical recurrence of prostate cancer (BCR), prompt tumor localization guides early treatment, potentially improving patient outcomes. Gallium-68 prostate-specific membrane antigen-11 positron emission tomography/computed tomography ([sup.68] Ga-PSMA-11 PET/CT) detection rates of lesions suspicious for prostate cancer are well known to rise along with prostate-specific antigen (PSA) concentration. However, published data are limited regarding very low values (≤0.2 ng/mL). We retrospectively analyzed ~7-year \"real-world\" experience in this setting in a large post-prostatectomy cohort (N = 115) from two academic clinics. Altogether 44 lesions were detected in 29/115 men (25.2%) (median [minimum-maximum] 1 [1-4]/positive scan). The apparent oligometastatic disease was found in nine patients (7.8%) at PSA as low as 0.03 ng/mL. Scan positivity rates were highest when PSA was >0.15 ng/mL, PSA doubling time was ≤12 months, or the Gleason score was ≥7b (in 83 and 107 patients, respectively, with available data); these findings were statistically significant (p ≤ 0.04), except regarding PSA level (p = 0.07). Given the benefits of promptly localizing recurrence, our observations suggest the potential value of [sup.68] Ga-PSMA-11 PET/CT in the very low PSA BCR setting, especially in cases with more rapid PSA doubling time or with high-risk histology.